The role of Fas-FasL-FADD signaling pathway in arsenic-mediated neuronal apoptosis in vivo and in vitro.

The molecular mechanisms underlying arsenic-induced neurotoxicity have not been completely elucidated. Our study aimed to determine the role of the Fas-FasL-FADD signaling pathway in arsenic-mediated neuronal apoptosis. Pathological and molecular biological tests were performed on the cerebral cortex of arsenic-exposed rats and SH-SY5Y neuroblastoma cells. Arsenic induced apoptosis in the cortical neurons, which corresponded to abnormal ultrastructural changes. Mechanistically, arsenic activated the Fas-FasL-FADD signaling pathway and the downstream caspases both in vivo and in vitro. ZB4 treatment reversed the apoptotic effects of arsenic on the SHSY5Y cells. Taken together, arsenic induces neurotoxicity by activating the Fas-FasL-FADD signaling pathway.

Selenite Downregulates STAT3 Expression and Provokes Lymphocytosis in the Liver of Chronically Exposed Syrian Golden Hamsters.

Arsenic is considered a worldwide pollutant that can be present in drinking water. Arsenic exposure is associated with various diseases, including cancer. Antioxidants as selenite and α-tocopherol-succinate have been shown to modulate arsenic toxic effects. Since changes in STAT3 and PSMD10 gene expression have been associated with carcinogenesis, the aim of this study was to evaluate the effect of arsenic exposure and co-treatments with selenite or α-tocopherol-succinate on the expression of these genes, in the livers of chronically exposed Syrian golden hamsters. Animals were divided into six groups: (i) control, (ii) chronically treated with 100 ppm arsenic, (iii) treated with 6 ppm α-tocopherol-succinate (α-TOS), (iv) treated with 8.5 ppm selenite, (v) treated with arsenic + α-TOS, and (vi) treated with arsenic + selenite. Urine samples and livers were collected after 20 weeks of continuous exposure. The urine samples were analyzed for arsenic species by atomic absorption spectrophotometry, and real-time RT-qPCR analysis was performed for gene expression evaluation. A reduction in STAT3 expression was observed in the selenite-treated group. No differences in PSMD10 expression were found among groups. Histopathological analysis revealed hepatic lymphocytosis in selenite-treated animals. As a conclusion, long-term exposure to arsenic does not significantly alter the expression of STAT3 and PSMD10 oncogenes in the livers of hamsters; however, selenite down-regulates STAT3 expression and provokes lymphocytosis.

Prepubertal arsenic exposure alters phosphoproteins profile, quality, and fertility of epididymal spermatozoa in sexually mature rats.

Arsenic intoxication affects male reproductive parameters of prepubertal rats. Besides, morphological and functional alterations in their testis and epididymis may remain after withdrawal of arsenic insult, causing potential impairment in male fertility during adulthood. In this study, we aimed at analyzing the effect of prepubertal arsenic exposure on the fecundity of epididymal sperm from sexually mature Wistar rats, assessing fertility indexes, sperm parameters, and sperm phosphoproteins content. Male pups on postnatal day (PND) 21 received filtered water (controls, n = 10) and 10 mg L-1 arsenite (n = 10) daily for 30 days. From PND52 to PND81, rats from both groups received filtered water. During this period, the males mated with non-exposed females between PND72 and PND75. Our results showed that sexually mature rats presented low sperm production, epididymal sperm count, motility, and quality after prepubertal arsenic exposure. These findings possibly contributed to the low fertility potential and high preimplantation loss. Epididymal sperm proteome detected 268 proteins, which 170 were found in animals from both control and arsenic groups, 27 proteins were detected only in control animals and 71 proteins only in arsenic-exposed rats. In these animals, SPATA 18 and other five proteins were upregulated, whereas keratin type II cytoskeletal 1 was downregulated (q < 0.1). The results of KEGG pathway analysis demonstrated an enrichment of pathways related to dopaminergic response, adrenergic signaling, protein degradation, and oocyte meiosis in arsenic-exposed animals. Moreover, 26 proteins were identified by phosphoproteomic with different phosphorylation pattern in animals from both groups, but SPATA18 was phosphorylated only in arsenic-exposed animals. We concluded that prepubertal exposure to arsenic is deleterious to sperm quality and male fertility, altering the sperm phosphoproteins profile.

Population Pharmacokinetics and Safety of Oral Tetra-Arsenic Tetra-Sulfide Formula in Pediatric Acute Promyelocytic Leukemia.

BACKGROUND: An oral tetra-arsenic tetra-sulfide (AS4S4) formula has been recommended as an outpatient post-remission treatment for Chinese adults with acute promyelocytic leukemia (APL) but limited data are available for children. In this exploratory study, we aimed to evaluate the pharmacokinetics and safety of the AS4S4 formula in children. METHODS: Eleven newly diagnosed and one relapsed pediatric patient (4-14 years of age) treated with the AS4S4 formula were included. Blood samples were collected from 12 children, and drug concentrations were quantified by ICP-MS. Population pharmacokinetic analysis and Monte-Carlo simulation were performed using NONMEM software. Toxic effects were graded according to the NCI-CTCAE, Version 3. RESULTS: A total of 107 arsenic concentrations (0.1-75.0 µg L-1) were used for population pharmacokinetic analysis. The median (range) of estimated weight-normalized CL and volume distribution at steady-state were 45.26 (35.63-82.18) L h-1 kg-1 and 230.37 (85.96-495.68) L kg-1, respectively. No patients discontinued AS4S4 treatment owing to adverse events, and there were no drug-related adverse events over grades 3-4. All newly diagnosed APL patients were in MCR with a median follow-up of 28 months (range, 23 to 37 months). Both the estimated 3-year EFS and OS rates were 100%. CONCLUSION: The pharmacokinetics and safety oral AS4S4 formula was evaluated for the first time in pediatric APL. The pharmacokinetic assessment demonstrated that the dosing regimen of 60 mg/kg/d TID resulted in a higher steady-state through concentration in children than that which was achieved in adults. The results of this study indicate that the AS4S4 formula is safe in newly diagnosed pediatric APL patients.

Essential concepts for interpreting the dose-response of low-level arsenic exposure in epidemiological studies.

Scientifically robust selections of epidemiological studies and assessments of the dose-response of inorganic arsenic in the low-dose range must consider key issues specific to arsenic in order to reduce risk of bias. The abundance of toxicological, mechanistic, and epidemiological evidence on arsenic enables a nuanced assessment of risk of bias in epidemiological studies of low-level arsenic, as opposed to a generic evaluation based only on standard principles. Important concepts in this context include 1) arsenic metabolism and mode of action for toxicity and carcinogenicity; 2) effects of confounding factors such as diet, health status including nutritional deficiencies, use of tobacco and other substances, and body composition; 3) strengths and limitations of various metrics for assessing relevant exposures consistent with the mode of action; and 4) the potential for bias in the positive direction for the observed dose-response relationship as exposure increases in the low-dose range. As an example, evaluation of a recent dose-response modeling using eight epidemiological studies of inorganic arsenic and bladder cancer demonstrated that the pooled risk estimate was markedly affected by the single study that was ranked as having a high risk of bias, based on the above factors. The other seven studies were also affected by these factors to varying, albeit lesser, degrees that can influence the apparent dose-response in the low-dose range (i.e., drinking water concentration of 65 µg/L or dose of approximately ≤1 µg/kg-day). These issues are relevant considerations for assessing health risks of oral exposures to inorganic arsenic in the U.S. population, and setting evidence-based regulatory limits to protect human health.

Effect of arsenic-containing hydrocarbon on the long-term potentiation at Schaffer Collateral-CA1 synapses from infantile male rat.

Arsenic-containing hydrocarbons (AsHCs) are common constituents of marine organisms and have potential toxicity to human health. This work is to study the effect of AsHCs on long-term potentiation (LTP) for the first time. A multi-electrode array (MEA) system was used to record the field excitatory postsynaptic potential (fEPSP) of CA1 before and after treatment with AsHC 360 in hippocampal slices from infantile male rats. The element content of Na, K, Ca, Mg, Mn, Cu, Zn, and As in the hippocampal slices were analyzed by elemental mass spectrometry after the neurophysiological experiment. The results showed that low AsHC 360 (1.5 µg As L-1) had no effect on the LTP, moderate AsHC 360 (3.75-15 µg As L-1) enhanced the LTP, and high AsHC 360 (45-150 µg As L-1) inhibited the LTP. The enhancement of the LTP by promoting Ca2+ influx was proved by a Ca2+ gradient experiment. The inhibition of the LTP was likely due to damage of synaptic cell membrane integrity. This study on the neurotoxicity of AsHCs showed that high concentrations have a strong toxic effect on the LTP in hippocampus slices of the infantile male rat, which may lead to a negative effect on the development, learning, and memory.

Changes induced by chronic exposure to high arsenic concentrations in the intestine and its microenvironment.

The perturbation of intestinal microbes may serve as a mechanism by which arsenic exposure causes or exacerbates diseases in humans. However, the changes in the intestinal microbiome and metabolome induced by long-term exposure to high concentrations of arsenic have not been extensively studied. In this study, C57BL/6 mice were exposed to sodium arsenite (As) (50 ppm) for 6 months. Our results show that long-term exposure to high As concentrations changed the structure of intestinal tissues and the expression of As resistance related genes in intestinal microbes. In addition, 16S rRNA gene sequencing revealed that As exposure significantly affected the Beta diversity of intestinal flora but had no significant effect on the Alpha diversity (except ACE index). Moreover, As exposure altered the composition of the intestinal microbiota from phylum to species. Non-targeted metabolomics profiling revealed that As exposure significantly changed the composition of metabolites, specifically those related to phenylalanine metabolism. Correlation analysis demonstrated that the changes in microbial communities and metabolites were highly correlated under As exposure. Overall, this study demonstrates that long-term exposure to high As concentrations disrupted the intestinal microbiome and metabolome, which may indicate the role of As exposure at inducing human diseases under similar conditions.

Bayesian benchmark dose analysis for inorganic arsenic in drinking water associated with bladder and lung cancer using epidemiological data.

Abundant epidemiological evidence has shown that there is a strong causal relationship between long-term exposure to inorganic arsenic (iAs) through drinking water and a few types of cancer (e.g., lung and bladder cancer). Traditionally, a linear low-dose extrapolation assumption was applied in risk assessment for iAs which resulted in a relatively conservative cancer risk estimate. Growing biological evidence suggests that the mode of action of iAs-induced cancer follows a threshold process (e.g., sufficient concentration of trivalent arsenic is required to disrupt normal cellular function). In this study, we applied the benchmark dose (BMD) methodology to model the relationship between the relative risk of bladder and lung cancer and the iAs concentration in drinking water using the high-quality epidemiological data reported in recently published papers, with a special focus on the low exposure range (i.e., <150 µg/L). Because of its biological plausibility and statistical flexibility, the Hill model has been chosen to model the data under a Bayesian framework. A Bayesian hierarchal model together with a bootstrap method for exposure estimation were applied to quantify uncertainty from various sources, including the within-study, between-study, and exposure uncertainties. Dose-response assessment results obtained from a number of alternative model structures and methods consistently demonstrate a threshold type dose-response curve with a threshold in the range between 40-60 µg/L of iAs concentration in drinking water. The BMD for iAs in drinking water associated with 0.1 % increase in relative risk of bladder cancer is 42.2 µg/L (BMDL 39.2 µg/L); for 0.05 % increase, the BMD is 41.6 µg/L (BMDL 38.6 µg/L). For lung cancer, the two counterpart BMD estimates are 57.0 µg/L (BMDL 43.6 µg/L) and 55.7 µg/L (BMDL 42.5 µg/L) for 0.1 % and 0.05 % increase, respectively. These analyses provide additional statistical support for a non-linear dose response for cancer risk from inorganic arsenic which may have important policy implications.

A review of low-dose arsenic risks and human cancers.

The linear no-threshold (LNT) model has historically been the default assumption in assessing carcinogenic risk from arsenic ingestion based on epidemiological studies. This contrasts with the threshold model used in assessing carcinogenic risk from arsenic ingestion derived from toxicological investigations of experimental animals. We present here a review of our epidemiological work that has examined models that may better explain the human cancer risk from the ingestion of arsenic, particularly from low level exposures, than does the LNT model. While previous epidemiology studies have demonstrated increased risks of bladder, lung, and skin cancers at arsenic exposures of 200 ug/L or greater, we seek here to examine the dose-response patterns at lower exposure levels. These include ecological, case/control, and cohort designs. Methodologic issues include choice of continuous or stratified analysis of exposure data, search for sources of non-conformity or variability, and distinctions in water sources and geography. Multiple studies have yielded useful data-based models, including threshold models, hockey-stick models, and "J-shaped" linear-quadratic models. These models have found that increased cancer risk may only begin at specific arsenic exposure levels greater than zero. These results provide guidance in seeking toxicological explanations and public health reference levels.

Dietary arsenic supplementation induces oxidative stress by suppressing nuclear factor erythroid 2-related factor 2 in the livers and kidneys of laying hens.

This study investigated the effects of dietary arsenic supplementation on laying performance, egg quality, hepatic and renal histopathology, and oxidative stress in the livers and kidneys of laying hens. Furthermore, the nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway was explored to reveal the molecular mechanism of the stress. Five hundred and twelve 40-week-old Hyline White laying hens were randomly allocated to 4 groups with 8 pens per group and 16 hens per pen. The doses of arsenic administered to the 4 groups were 0.95, 20.78, 40.67, and 60.25 mg/kg. The results revealed that dietary arsenic supplementation significantly reduced hen-day egg production (P < 0.05), average egg weight (P < 0.05), Haugh units (P < 0.05), albumen height (P < 0.05), and eggshell strength (P < 0.05). Dietary arsenic supplementation also induced the accumulation of arsenic and histopathological damages in the liver and kidney. In accordance, dietary arsenic supplementation significantly enhanced serum alanine aminotransferase (P < 0.05), aspartate aminotransferase (P < 0.05), blood urea nitrogen (P < 0.05), and uric acid (P < 0.05) levels. After arsenic exposure, the activities of superoxide dismutase (SOD) (P < 0.05), catalase (P < 0.01), glutathione reductase (P < 0.05), and glutathione peroxidase (P < 0.05), and glutathione content (P < 0.05) were significantly decreased, while the malondialdehyde level was significantly increased (P < 0.05) in the liver and kidney. Positive correlations occurred between antioxidant enzyme activities and antioxidant enzyme gene expressions in the liver and kidney, except for renal manganese superoxide dismutase gene expression and SOD activity. Additionally, hepatic and renal Nrf2 mRNA expression was positively correlated with antioxidant gene expressions and negatively correlated with Keap1 mRNA expression. In summary, dietary arsenic supplementation induced oxidative stress by suppressing the Nrf2-Keap1 pathway in the livers and kidneys of laying hens.

The burden of disease of three food-associated heavy metals in clusters in the Danish population - Towards targeted public health strategies.

Lifestyle and sociodemographics are likely to influence dietary patterns, and, as a result, human exposure to chemical contaminants in foods and their associated health impact. We aimed to characterize subgroups of the Danish population based on diet and sociodemographic indicators, and identify those bearing a higher disease burden due to exposure to methylmercury (MeHg), cadmium (Cd) and inorganic arsenic (i-As). We collected dietary, lifestyle, and sociodemographic data on the occurrence of chemical contaminants in foods from Danish surveys. We grouped participants according to similarities in diet, lifestyle, and sociodemographics using Self-Organizing Maps (SOM), and estimated disease burden in disability-adjusted life years (DALY). SOM clustering resulted in 12 population groups with distinct characteristics. Exposure to contaminants varied between clusters and was largely driven by intake of fish, seafood and cereal products. Five clusters had an estimated annual burden >20 DALY/100,000. The cluster with the highest burden had a high proportion of women of childbearing age, with most of the burden attributed to MeHg. Individuals belonging to the top three clusters had higher education and physical activity, were mainly non-smokers and lived in urban areas. Our findings may facilitate the development of preventive strategies targeted to the most affected subgroups.

Using the Metabolome to Understand the Mechanisms Linking Chronic Arsenic Exposure to Microglia Activation, and Learning and Memory Impairment.

The activation of microglia is a hallmark of neuroinflammation and contributes to various neurodegenerative diseases. Chronic inorganic arsenic exposure is associated with impaired cognitive ability and increased risk of neurodegeneration. The present study aimed to investigate whether chronic inorganic arsenic-induced learning and memory impairment was associated with microglial activation, and how organic (DMAV 600 µM, MMAV 0.1 µM) and inorganic arsenic (NaAsO2 0.6 µM) affect the microglia. Male C57BL/6J mice were divided into two groups: a control group and a group exposed to arsenic in their drinking water (50 mg/L NaAsO2 for 24 weeks). The Morris water maze was performed to analyze neuro-behavior and transmission electron microscopy was used to assess alterations in cellular ultra-structures. Hematoxylin-eosin and Nissl staining were used to observe pathological changes in the cerebral cortex and hippocampus. Flow cytometry was used to reveal the polarization of the arsenic-treated microglia phenotype and GC-MS was used to assess metabolomic differences in the in vitro microglia BV-2 cell line model derived from mice. The results showed learning and memory impairments and activation of microglia in the cerebral cortex and dentate gyrus (DG) zone of the hippocampus, in mice chronically exposed to arsenic. Flow cytometry demonstrated that BV-2 cells were activated with the treatment of different arsenic species. The GC-MS data showed three important metabolites to be at different levels according to the different arsenic species used to treat the microglia. These included tyrosine, arachidonic acid, and citric acid. Metabolite pathway analysis showed that a metabolic pathways associated with tyrosine metabolism, the dopaminergic synapse, Parkinson's disease, and the citrate cycle were differentially affected when comparing exposure to organic arsenic and inorganic arsenic. Organic arsenic MMAV was predominantly pro-inflammatory, and inorganic arsenic exposure contributed to energy metabolism disruptions in BV-2 microglia. Our findings provide novel insight into understanding the neurotoxicity mechanisms of chronic arsenic exposure and reveal the changes of the metabolome in response to exposure to different arsenic species in the microglia.

Does arsenic pose a health concern after consumption of clay products?

Clay products for oral use form a particular group of food supplements in relation to potential arsenic (As) toxicity, because - certainly in case of pure clay- all arsenic in these supplements is expected to be present in the most toxic inorganic form (Asi). In terms of risk, the most important questions to answer relate to the bioaccessibility and bioavailability of the inorganic arsenic present, rather than to the As species distribution, which often receives most attention in standard foodstuffs. In the present study, clay products for oral use were bought on the Belgian market and analysed for total arsenic (Astot), arsenic species (Asi, arsenobetaine, dimethylarsenate and monomethylarsenate)) and bioaccessible arsenic, in order to perform an exposure assessment and risk characterisation. Total As concentrations differed considerably between the samples and ranged from 0.20 to 6.4 mg Astot/kg. Bioaccessibility of Asi, determined via the Unified Barge Method (extraction making use of digestive enzymes) varied between 8% and 51%. The Asi concentration determined via HPLC-ICP-MS after extraction with diluted HNO3 + H2O2 (as in the CEN method for foodstuffs) was only a poor predictor of the bioaccessible Asi fraction, despite the significant relationship (R2 = 0.36; p < .05). The risk characterisation did not reveal acute risks related to Asi exposure. However, a potential concern with regard to chronic Asi intake was identified for the general population in 42% of the analysed food supplements, and for sensitive population groups in 67% of the samples, even after taking into account the bioaccessible fraction. The data presented illustrate that consumption of some of these clay products may contribute significantly to dietary Asi intake and that these should not be taken chronically.

Feeding Arsenic-Containing Rice Bran to Growing Pigs: Growth Performance, Arsenic Tissue Distribution, and Arsenic Excretion.

This research was conducted to study the growth performance, arsenic (As) tissue distribution, and As excretion of pigs fed As-containing rice bran. Twenty gilts (26.3 kg) were randomly assigned to 3 dietary treatments (n = 6 or 7) with Diets I, II, and III containing 0, 36.7, and 73.5% rice bran and 0, 306, and 612 ppb As, respectively. Pigs were fed for 6 weeks, and their growth performance and daily activities were examined. Fecal, blood, and hair samples were collected immediately before and after the 6-weeks. At the end of the 6-weeks, pigs were slaughtered; the liver, kidney, muscle, and urine samples were collected. No pig showed any unhealthy signs throughout the trial. The average daily feed intake, average daily gain, and final body weight of Diet III pigs were lower (p ≤ 0.001) than Diet I pigs. The gain to feed ratios were not different among the treatments. The fecal, hair, kidney, and urinary As concentrations of both Diets II and III pigs were higher than Diet I pigs. The hair As concentration of Diet III pigs was higher than Diet II pigs, but no difference was found in the fecal, urinary, kidney, or muscle As concentrations between Diets II and III pigs. The blood and muscle As concentrations were below 10 ppb. These results suggest that 73.5% dietary rice bran inclusion compromised growth performance, whereas the 36.7% inclusion did not. The fecal As data imply that dietary As was poorly absorbed by the gastrointestinal tract. The tissue As data indicate that the absorbed As was rapidly cleared from the blood with some retained in various organs and others eliminated via urine. The hair As concentration was much higher than that of liver and kidney. The muscle As data suggest that the pork produced from the pigs fed a typical As-containing rice bran as used in this study is safe for human consumption.

Phytoremedial effect of Tinospora cordifolia against arsenic induced toxicity in Charles Foster rats.

Arsenic poisoning is one of the most serious health hazards of recent times. It has been estimated that more than 200 million people of about 105 countries in the world are affected due to arsenic poisoning. Except mitigation, there is no such mode by which the population can be prevented from being exposed to arsenic. Tinospora cordifolia (T. cordifolia) is widely used in the folk medicine system for the treatment of various diseases. Hence, the aim of the present study was to investigate the antidote effects of ethanolic extract of T. cordifolia stem against arsenic induced hepato-renal toxicity in rat model. Twenty-four male Charles Foster rats (weighing 160-180 g) were randomly divided into two groups, where six rats were used as control group. Eighteen rats were orally treated with arsenic at the dose of 8 mg/kg body weight for 90 days daily and then further divided into three sub groups (n = 6 each). Sub group I-arsenic treated rats, were sacrificed after treatment; sub group II rats were used as arsenic control and the sub group III rats were administrated with T. cordifolia at the dose of 400 mg/kg body weight/day for 90 days. After the completion of dose duration, all the control and treatment group rats were sacrificed to evaluate the various parameters. Arsenic induced rats had significantly (p < 0.0001) altered biochemical serum levels of SGPT, SGOT, ALP, total bilirubin, urea, uric acid, creatinine and albumin; But, after the administration of T. cordifolia there was significant (p < 0.0001) restoration observed in these liver and kidney function parameters. The T. cordifolia administration also significantly (p < 0.0001) restored the serum MDA levels and arsenic concentration in blood, liver and kidney tissues, as well as significant (p < 0.0001) improvement in haematological variables. In histopathological study, the arsenic treated rats showed degenerative changes in the liver and kidney tissues such as lesions and vacuolizations in hepatocytes and nephrocytes respectively. However, after the administration with T. cordifolia rats, there was considerably significant restoration in liver and kidney tissues. The entire study suggests that arsenic caused severe damage to the liver and kidney at haematological, biochemical and histopathological levels in rats. However, T. cordifolia played the vital role to combat the arsenic induced toxicity in rats. Hence, T. cordifolia might be used as a nutritional supplement to combat the arsenic led toxicity among the exposed population.

A Simplified Questionnaire for the Assessment of Inorganic Arsenic Intake in a Japanese Population.

A simplified questionnaire was developed to assess inorganic arsenic (iAs) intake level in a Japanese population. The two page questionnaire included photographs of single serving sizes of rice and cooked hijiki (Hizikia fusiforme: brown algae), and asked subjects about the number of servings of rice and cooked hijiki, two predominant dietary sources of iAs in Japan, they consume in a day. Daily intake of iAs was estimated for 72 Japanese subjects using the questionnaire together with data of iAs content in rice and hijiki seaweed, and the estimated intakes were compared with actual iAs intakes of the subjects as measured for a duplicate diet using liquid chromatography-inductively coupled plasma mass spectrometry. A highly significant correlation was found between the estimated and measured intakes (r = 0.65, p < 0.001); however, the slope of regression indicated a systematic error in the intake estimation. Possible sources of error are discussed herein. It was concluded that this approach is promising if minor improvements are made to the questionnaire.

Doping control analysis of total arsenic in equine plasma.

Arsenic can be easily found in our surrounding environment. Because of its ubiquitous nature, horse urine and blood invariably contain low levels of arsenic. Nevertheless, inorganic arsenic, despite its general use as a tonic for horses, is an effective doping agent having a deleterious effect because of its ability to induce gastroenteritis. The misuse of arsenic in horseracing has been controlled by an international urinary threshold of total arsenic at 0.3 µg/mL. However, an equivalent threshold for total arsenic in plasma is yet to be established. In this study, an inductively coupled plasma-mass spectrometry method has been developed for quantifying total arsenic in equine plasma. Statistical analysis determined that the data from a population study of 1,552 post-race and out-of-competition plasma samples fits a Gaussian mixture model with two Gaussian components. A rounded-up provisional threshold for plasma total arsenic at 2.5 ng/mL was subsequently established. Results from administration trials with a sodium arsanilate-containing supplement showed that both urinary and plasma arsenic was significantly elevated after administration. The maximum urinary detection time was around 22 h based on the international threshold. However, the maximum plasma detection time would be longer than 73 h if the provisional threshold of 2.5 ng/mL was adopted. In view of the high discrepancy between the urine and plasma detection times, a revised plasma threshold of 15 ng/mL is proposed to afford a comparable detection time in both matrices. The risk of a normal sample exceeding the proposed plasma total arsenic threshold is practically zero.

Arsenic induces dose-dependent structural and ultrastructural pathological remodeling in the heart of Wistar rats.

AIM: Arsenic, an environmental contaminant, represents a public health problem worldwide. Studies have shown its association with molecular mechanisms related to cardiomyocytes redox balance. However, the microstructure and ultrastructure of cardiac tissue, as well as the activity of its antioxidant defenses front of disturbances in the mineral bioavailability induced by arsenic are still scarce. Thus, the aim of this study was to evaluate if arsenic exposure might induce structural and ultrastructural damages in cardiac tissue, including pathological remodeling of the parenchyma and stroma. Moreover, its impact on micromineral distribution and antioxidant enzymes activity in heart tissue was also evaluated. MAIN METHODS: Adult male Wistar rats were divided into three groups that received 0, 1 and 10 mg/L sodium arsenite in drinking water for eight weeks. The hearts were collected and subjected to structural and ultrastructural analysis, mineral microanalysis and antioxidant enzymes quantification. Functional markers of cardiac damages were evaluated using serum samples. KEY FINDINGS: Arsenic exposure induced dose-dependent structural and ultrastructural remodeling of cardiac tissue, with parenchyma loss, increase of stroma components, collagen deposition, and pathological damages such as inflammation, sarcomere disorganization, mitochondria degeneration and myofilament dissociation. Moreover, this metalloid was bioaccumulated in the tissue affecting its micromineral content, which resulted in antioxidant imbalance and increased levels of oxidative stress and cardiac markers. SIGNIFICANCE: Taken together, our findings indicate that the heart is a potential target to arsenic toxicity, and long-term exposure to this metalloid must be avoided, once it might induce several cardiac tissue pathologies.

Metabolism of Inorganic Arsenic in Mice Lacking Genes Encoding GST-P, GST-M, and GST-T.

To investigate the role of glutathione transferases (GSTs) in the metabolism of inorganic arsenic (iAs), we compared the disposition of iAs and its metabolites in wild-type mice and mice lacking genes encoding GST-P, -M and -T after exposure to 100 ppb iAs in drinking water. We found no differences between the two genotypes in the concentrations of total arsenic or arsenic species in urine, liver, and kidneys. No genotype-dependent differences were found in proportions of arsenicals in the tissues, and only small differences were observed in the urine. Thus, under these conditions, GST-P, -M and -T did not play a significant role in iAs metabolism in mice.

Arsenic Exposure and Compromised Protein Quality Control.

Exposure to arsenic in contaminated drinking water is a worldwide public health problem that affects more than 200 million people. Protein quality control constitutes an evolutionarily conserved mechanism for promoting proper folding of proteins, refolding of misfolded proteins, and removal of aggregated proteins, thereby maintaining homeostasis of the proteome (i.e., proteostasis). Accumulating lines of evidence from epidemiological and laboratory studies revealed that chronic exposure to inorganic arsenic species can elicit proteinopathies that contribute to neurodegenerative disorders, cancer, and type II diabetes. Here, we review the effects of arsenic exposure on perturbing various elements of the proteostasis network, including mitochondrial homeostasis, molecular chaperones, inflammatory response, ubiquitin-proteasome system, autophagy, as well as asymmetric segregation and axonal transport of misfolded proteins. We also discuss arsenic-induced disruptions of post-translational modifications of proteins, for example, ubiquitination, and their implications in proteostasis. Together, studies in the past few decades support that disruption of protein quality control may constitute an important mechanism underlying the arsenic-induced toxicity.